High density lipoprotein (HDL) plays a critical role in preventing CVD. Inflammation is of central importance in the pathogenesis of atherosclerosis. Chronic inflammation leads to changes in HDL [e.g. decreased apolipoprotein A-l (apo A-l) and paraoxonase (PON1), and increased SAA and other novel proteins identified by mass spectrometry]. These changes are associated with a loss of its atheroprotective properties. Inflammation also may lead to pro-atherogenic changes in HDL. We hypothesize that compositional and functional changes in HDL induced by inflammation provides an important link between inflammation and atherosclerosis. We also hypothesize that changes in HDL composition may be biomarkers that indicate the presence of oxidative damage and/or atherosclerosis at the level of the artery wall. To test these hypotheses, we plan to determine how inflammation (acute and chronic) influences HDL composition, function and role in atherogenesis in mice. Next, we will test the mechanism by which inflammation reduces the atheroprotective HDL apolipoproteins apo A-l and PON1, and increases the potentially proatherogenic apolipoprotein SAA in HDL. Third, we will determine whether local over-expression by macrophages of inflammatory and anti-inflammatory proteins present in HDL affects the initiation and/or progression of atherosclerosis in a mouse model of hypercholesterolemia. Finally, we will determine whether chronic inflammation alters the composition and functional properties of HDL in humans in a manner similar to that in mice, and whether changes in HDL protein composition are markers of oxidation and/or atherosclerosis Many of these studies will involve the use of novel mass spectrometric approaches. These studies should provide important information to our longterm goal of understanding the relationship between inflammation, lipoprotein metabolism and atherosclerosis.